Coverage Policy Manual
Policy #: 2016017
Category: Pharmacy
Initiated: July 2016
Last Review: July 2022
  Radium Ra 223 dichloride for Symptomatic Osseous Metastatic Prostate Cancer (e.g., Xofigo®; Ra 223)

Description:
Radium Ra 223 dichloride is an alpha particle emitting radiopharmaceutical that is indicated for the treatment of patients with castration resistant prostate cancer, symptomatic bone metastases, and no known visceral metastases. Radium is a bone-seeking element, and its decay allows the deposition of high energy radiation over a much shorter distance than with beta particle emitting radioisotopes, thus potentially treating tumor while minimizing toxicity to normal bone marrow.
 
Radium Ra 223 dichloride injection is  an alpha particle-emitting radioactive therapeutic agent which mimics calcium to bind with bone minerals in areas of bone metastases. The agent has an anti-tumor effect which occurs due to energy transfer from the radioactive material to nearby cancer cells.

Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize a radiation oncology benefits management program, Prior Approval is required for this service and is managed through the radiation oncology benefits management program.
 
Effective July 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
A single course of Radium Ra 223 dichloride as monotherapy, up to 6 planned monthly injections meets primary coverage criteria for treatment of prostate cancer when ALL of the following criteria are met:
 
    • Individual is age 18 years or older
    • Individual has a good performance status (ECOG 0-2) (FDA, 2019)
    • Metastatic, castrate-resistant prostate cancer
    • Serum testosterone level is less than 50 ng/dl (NCCN, 2021)
    • Symptomatic bone metastases only, with no visceral involvement (FDA, 2019)
    • No bulky (>3 cm) lymph node metastases
    • Disease is worsening or progressing and ANY of the following conditions are met (NCCN, 2021):
        • Based on imaging demonstrating worsening bone metastases
        • Based on PSA over 5 mg/mL and rising over 2 consecutive lab evaluations
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
The dose regimen of radium Ra 223 dichloride is administered at 55 kBq (1.49 microcurie) per kg body weight, given at 4 week intervals for 6 injections.
 
Single-use vial at a concentration of 1,100 kBq/mL (30 microcurie/mL) at the reference date with a total radioactivity of 6,600 kBq/vial (178 microcurie/vial) at the reference date.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Radium Ra 223 dichloride for the treatment of prostate cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following:
    • The above criteria are not met and for all other indications
    • Given as a repeat course of treatment
    • Systemic radiotherapy with radioisotopes given within the previous 24 weeks
    • Chemotherapy or biologic therapy given within the previous 4 weeks
    • Used concurrently with other chemotherapy, biologic therapy, or abiraterone (Note: This does not include androgen-ablation therapy or other hormonal therapy unless otherwise specified)
    • There is evidence of spinal cord compression
 
Note: Radium 223 cannot be combined with chemotherapy or biologic therapy; however, it can be combined with hormonal agents or ablation.
 
For members with contracts without primary coverage criteria, the use of Radium 223 dichloride for the treatment of prostate cancer in any other circumstance or for any other indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective July 2019 to June 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Radium Ra 223 dichloride (Xofigo) meets primary coverage criteria for treatment of prostate cancer when ALL of the following criteria are met:
 
    • The patient has castration-resistant prostate cancer; AND  
    • symptomatic bone metastases; AND   
    • no known visceral metastatic disease; AND
    • has not received systemic radiotherapy with radioisotopes within the previous 24 weeks; AND
    • no evidence of imminent or established spinal cord compression; AND
    • has not been treated with chemotherapy or biologic therapy within the previous 4 weeks and will not be concurrently receiving chemotherapy or biologic therapy (Note: this does not include androgen-ablation therapy or other hormonal therapy) for prostate cancer.
 
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
 
Dosage and Administration
The dose regimen of radium Ra 223 dichloride (Xofigo) is administered at 50 kBq (1.35 microcurie) per kg body weight, given at 4 week intervals for 6 injections.
Single-use vial at a concentration of 1,000 kBq/mL (27 microcurie/mL) at the reference date with a total radioactivity of 6,000 kBq/vial (162 microcurie/vial) at the reference date.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Radium Ra 223 dichloride (Xofigo) for the treatment of prostate cancer does not meet member benefit certificate primary coverage criteria for the treatment of prostate cancer in any other circumstance or for any other indication.
 
For members with contracts without primary coverage criteria, the use of Radium 223 dichloride for the treatment of prostate cancer in any other circumstance or for any other indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective July 2016 to June 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Radium Ra 223 dichloride (Xofigo) meets primary coverage criteria for treatment of prostate cancer when ALL of the following criteria are met:
    • The patient has castration-resistant prostate cancer; AND  
    • symptomatic bone metastases; AND  
    • no known visceral metastatic disease; AND
    • has not received systemic radiotherapy with radioisotopes within the previous 24 weeks; AND
    • no evidence of imminent or established spinal cord compression; AND
    • has not been treated with chemotherapy or biologic therapy within the previous 4 weeks and will not be concurrently receiving chemotherapy or biologic therapy (Note: this does not include androgen-ablation therapy or other hormonal therapy) for prostate cancer.
 
Policy Guidelines:
The dose regimen of radium Ra 223 dichloride (Xofigo) is administered at 50 kBq (1.35 microcurie) per kg body weight, given at 4 week intervals for 6 injections.
 
Single-use vial at a concentration of 1,000 kBq/mL (27 microcurie/mL) at the reference date with a total radioactivity of 6,000 kBq/vial (162 microcurie/vial) at the reference date
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Radium Ra 223 dichloride (Xofigo) for the treatment of prostate cancer does not meet member benefit certificate primary coverage criteria for the treatment of prostate cancer in any other circumstance or for any other indication.
 
For members with contracts without primary coverage criteria, the use of Radium 223 dichloride for the treatment of prostate cancer in any other circumstance or for any other indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
The FDA approval was based in part on the interim analysis of the results of the ALSYMPCA trial, a multicenter, phase III, double blind study that randomized 809 participants with CRPC and bone metastases to receive either radium-223 (n=541) or placebo (n=268) (Parker, 2013). Castrate-resistant prostate cancer was defined as a serum testosterone level of 50 ng per deciliter or lower (less than or equal to 1.7 nmol per liter) after bilateral orchiectomy or after maintenance treatment consisting of androgen-ablation therapy with a leuteinizing hormone-releasing hormone agonist or polyestradiol phosphate. Additionally, all participants had symptomatic bone disease requiring the regular use of analgesic medicine or treatment with external-beam radiation therapy. Other eligibility criteria included PSA level of 5 ng per milliliter or higher with evidence of progressively increasing PSA values, ECOG performance-status score of 0 to 2, adequate hematologic, renal and liver function, and life expectancy of 6 months or longer. Participants were excluded from the study if they had visceral disease or received chemotherapy within the prior 4 weeks or had not recovered from adverse events due to chemotherapy, previous hemibody external radiotherapy, systemic radiotherapy with radioisotopes within the prior 24 weeks, a blood transfusion or use of erythropoietin-stimulating agents within the prior 4 weeks, a malignant lymphadenopathy 3 cm or more in the short-axis diameter, a history of or the presence of visceral metastases, and imminent or established spinal cord compression. The radium-223 group showed significant improvement in overall survival compared to placebo (median 14.0 months versus 11.2 months; hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.58 to 0.83; p<0.001).
 
Radium-223 increased both overall survival and the time to first symptomatic skeletal related event in the phase III ALSYMPCA trial. Symptomatic skeletal events were defined as external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention.
 
In the ALSYMPCA trial, all patients had castration resistant prostate cancer with multiple bone metastases and had either progressed on docetaxel chemotherapy or were not candidates for docetaxel chemotherapy (Parker, 2013). Patients were required to have two or more bone metastases and no known visceral metastases. Overall, 921 patients were randomly assigned in a 2:1 ratio to best supportive care plus radium-223 (one dose every four weeks for six cycles) or best supportive care plus placebo. Best supportive care options included a second-line variety of hormonal therapies and bisphosphonates. Approximately 80 percent had six or more lesions on bone scan and 40 percent had 20 or more lesions. Almost 60 percent had received prior docetaxel chemotherapy. The clinical trial used six doses of radium-223 every four weeks; there are no safety or efficacy data on additional doses of treatment.
 
Overall survival, the primary endpoint of the trial, was significantly prolonged compared with placebo (median 14.9 versus 11.3 months, HR 0.70, 95% CI 0.58-0.83).  The survival benefit was consistent across all patient subgroups, including both those who had and had not received prior docetaxel. The time to first symptomatic skeletal event (SSE, which included the first use of external beam RT for symptom relief, new pathologic fracture, spinal cord compression, or tumor related orthopedic surgery intervention) was significantly increased (median 15.6 versus 9.8 months, HR 0.66, 95% CI 0.52-0.83) [2]. When the symptomatic skeletal events were analyzed individually, the differences were statistically significant for use of external beam RT for symptom relief (HR 0.67) and for spinal cord compression (HR 0.52). Differences were not statistically significant for new pathologic fracture (0.62) or for orthopedic surgery intervention (0.72), but the number of such events was limited. Routine radiographs were not utilized during this trial, and thus all SSEs were detected clinically. Treatment was associated with a favorable safety profile, with a lower frequency of all adverse events compared with placebo; there were no clinically meaningful differences in the incidence of grade 3 or 4 adverse events. In a prespecified subset analysis, radium-223 had similar efficacy in those who had received prior docetaxel and those who were docetaxel naïve Treatment was well tolerated irrespective of prior docetaxel use, although the incidence of grade 3-4 thrombocytopenia was higher in patients who had previously received docetaxel (9 versus 3 percent).Treatment with was associated with a better quality of life during the period of study drug administration.
 
FDA prescribing information states Xofigo is to be given at 4 week intervals for a total of 6 injections (U.S. Food and Drug Administration, 2016).
 
2019 Update
A literature search conducted through June 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
A9606Radium ra 223 dichloride, therapeutic, per microcurie

References: American Cancer Society.(2015) Prostate cancer. How is prostate cancer staged? March 12, 2015. Available at: http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-survival-rates. Accessed on July 7, 2016.

National Cancer Institute.(2013) Radium-223 improves survival in patients with advanced prostate cancer. August 2, 2013. Available at: http://www.cancer.gov/clinicaltrials/results/summary/2013/radium-223-ALSYMPCA. Accessed on July 7, 2016.

U.S. Food and Drug Administration.(2013) FDA news release. FDA approves new drug for advanced prostate cancer. May 15, 2013. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm352363.htm. Accessed on July 8, 2016.

American Cancer Society.(2015) Overview: prostate cancer. Revised March 3, 2010. Available at: http://www.cancer.org/cancer/prostatecancer/overviewguide/index. Accessed on July 7, 2016.

National Comprehensive Cancer Network (NCCN).(2021) Clinical practice guidelines in oncology. Prostate cancer, version 2.2021. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

Parker C., Nilsson D., Heinrich S.I., et al.(2013) Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369:213-223.

Prostate Cancer (PDQ®). July 2015.(2015) 3. National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/prostate/Patient. Accessed on July 7, 2016.

U.S. Food and Drug Administration.(2016) Full Prescribing Information. Revised March 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203971s007lbl.pdf. Accessed July 8, 2016.

U.S. Food and Drug Administration.(2019) Xofigo (radium Ra 223 dichloride) Full Prescribing Information. Revised 12/2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/203971s016lbl.pdf.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2023 American Medical Association.